Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery

Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins.

 

Comments:

The provided passage describes a study that focuses on overcoming multidrug resistance in cancer by inhibiting ABC transporters, specifically ABCG2 and P-glycoprotein (P-gp). The researchers report the characterization of a potent ABCG2 inhibitor called chromone 4a (C4a). They conducted molecular docking and in vitro assays using membrane vesicles expressing ABCG2 and P-gp from insect cells. The results showed that C4a interacted with both transporters but exhibited selectivity towards ABCG2 in cell-based transport assays.

C4a effectively inhibited the ABCG2-mediated efflux of various substrates. Molecular dynamic simulations indicated that C4a bound within the Ko143-binding pocket, a known site for ABCG2 inhibition. To address the issue of C4a's poor water solubility and delivery, the researchers employed liposomes and extracellular vesicles (EVs) derived from Giardia intestinalis and human blood. These carriers successfully facilitated the delivery of C4a and inhibited ABCG2 function.

Furthermore, the study demonstrated the potential use of plasma circulating EVs for delivering hydrophobic drugs that target membrane proteins. They also showed that human blood EVs enabled the delivery of elacridar, a well-known P-gp inhibitor.

Overall, this research highlights the promising role of C4a as an ABCG2 inhibitor and suggests the use of plasma circulating EVs as a means of delivering hydrophobic drugs that target membrane proteins, which could aid in overcoming multidrug resistance in cancer treatment.

Related Products

Cat.No.	Product Name	Information
S7772	Elacridar (GF120918)	Elacridar (GF120918, GW120918, GG918, GW0918) is a potent P-gp (MDR-1) and BCRP inhibitor.

Related Targets

P-gp